Gila monsters can eat up to a third of their body weight in one sitting. Humans cannot. So what makes us different? Beyond our obvious lack of scales and a tail, humans do not have the hormone exendin-4 in our saliva. Exendin-4 allows Gila monsters to eat enormous quantities of food while maintaining a functional metabolism and stable glucose levels. This molecule is, however, analogous to GLP-1s, or glucagon-like peptides, in humans. The development of exendin-4 into the diabetes drug exenatide started the GLP-1RA, or GLP-1 receptor agonist, race.
GLP-1RAs are synthetic molecules that mimic the effects of the naturally-occurring GLP-1 hormone, including increasing insulin secretion and slowing gastric emptying. These molecules, which have made waves in the treatment of obesity and Type 2 diabetes through medications such as Ozempic, Wegovy and Zepbound, are more stable than their natural counterparts, thus increasing their therapeutic potential.
GLP-1RAs act via a multitude of mechanisms in the gut and the pancreas. In the gut, they decrease secretion of ghrelin (the ‘hunger hormone’) and increase peptide YY and cholecystokinin levels. Through the regulation of these hormones, GLP-1RAs slow gastric emptying, reduce appetite and promote digestion. In the pancreas, GLP-1RAs enhance insulin secretion and inhibit the release of glucagon, a hormone that induces the breakdown of stored sugars into the bloodstream.
Perhaps most interesting, though, are the changes GLP-1RAs induce in the brain. Beyond increasing appetite-suppressing hormones and peptides, GLP1-RAs act on the mesolimbic reward pathway. GLP-1 receptors are present in two critical portions of this pathway: the ventral tegmental area and nucleus accumbens. The VTA, located in the midbrain, plays an important role in reward and addiction by modulating how much dopamine is sent to the NAc. The NAc then receives the dopamine and plays a key role in cost-benefit analysis and risk-reward decision making. By attaching to GLP-1 receptors on these structures, GLP-1RAs decrease dopamine release and therefore make addictive behaviors less rewarding.
This mechanism raises a question: If GLP-1RAs impact reward pathways, can they be effectively used to treat addiction disorders? According to a number of recent studies, they can. During phase 2 clinical trials, semaglutide reduced alcohol cravings, leading to fewer drinks consumed per day. Conversely, a study of the GLP-1RA exenatide demonstrated that, while the drug reduced alcohol craving and consumption in obese participants, it increased heavy drinking days in lean individuals. GLP-1RAs have shown similar promise in reducing nicotine cravings, in part due to their mitigation of the weight gain commonly associated with smoking cessation.
Arguably more impressive than the effect GLP-1RAs have on alcohol and nicotine use disorders is their impact on opioid cravings. The opioid crisis has been an ongoing issue in the United States, with nearly 76% of total overdose deaths coming from opioids such as heroin, fentanyl and oxycodone. A recent clinical trial, however, demonstrated a 40% reduction in opioid cravings and an overall decrease in self-administration with the GLP-1RA liraglutide.
People seeking to treat a substance use disorder with GLP-1RAs face a massive barrier to entry, though: This treatment is still off-label, meaning insurance will not cover it. Without support from insurance, these drugs can cost up to $16,000 per year. This exorbitant cost makes GLP-1RAs inaccessible to most, and it likely won’t be changing soon. The lack of large, randomized controlled trials makes it unlikely for SUD to become an on-label use anytime soon. Current GLP-1RA treatments will also likely retain their patents into the 2030s, reducing competition and preventing consumers from driving down prices.
Opioid overdose is also highly associated with markers of low socioeconomic status such as unemployment, lack of a college education and lack of health insurance. This means the people most vulnerable to overdose are least able to seek this new treatment. SUD, already a social disease, may become even further rooted in socioeconomic standing.
This is not the path addiction treatment has to take, though. In 2020, the opioid crisis cost the United States nearly $1.5 trillion. In 2024, the United States budgeted nearly $44.5 billion for drug control. These costs could instead be redirected to deliver new, increasingly effective treatments like GLP-1RAs to those most in need, reducing the burden of substance abuse for communities across the country.
